US20110027396A1 - Novel milk thistle extract, method for the production, and use - Google Patents

Novel milk thistle extract, method for the production, and use Download PDF

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Publication number
US20110027396A1
US20110027396A1 US12/810,178 US81017808A US2011027396A1 US 20110027396 A1 US20110027396 A1 US 20110027396A1 US 81017808 A US81017808 A US 81017808A US 2011027396 A1 US2011027396 A1 US 2011027396A1
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Prior art keywords
extract
milk thistle
thistle fruit
liver
fruit extract
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Astrid Nagell
Jaime Xiol Aguirre
Santiago Rull Prous
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Madaus GmbH
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Euromed SA
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Assigned to EUROMED S.A. reassignment EUROMED S.A. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: AQUIRRE, JAIME XIOL, NAGELL, ASTRID, PROUS, SANTIAGO RULL
Publication of US20110027396A1 publication Critical patent/US20110027396A1/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/28—Asteraceae or Compositae (Aster or Sunflower family), e.g. chamomile, feverfew, yarrow or echinacea
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P39/00—General protective or antinoxious agents
    • A61P39/02—Antidotes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2236/00—Isolation or extraction methods of medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicine
    • A61K2236/30—Extraction of the material

Definitions

  • the present invention relates to a method for preparing a milk thistle fruit extract, in particular a flavanolignan preparation having an increased release rate and improved absorbability, and use thereof, in particular for the treatment and prevention of liver diseases.
  • the milk thistle ( Silybum marianum or Carduus marianus ) is a plant which is cultivated in particular in southwest and central Europe (Austria, Hungary), and which has become naturalized in Eurasia, North America, South America, and Australia. Production areas are also found in China.
  • the efficacy of the drug from milk thistle (seeds and fruit) in the treatment and prevention of various forms of liver and gall bladder dysfunction is known.
  • the drug is composed of the ripe fruit from which the pulp has been removed, having a minimum sylimarin content of 1.5% (Pharmacopoea Europaea (Ph. Eur.), 2007).
  • Tinctures usually alcoholic extracts of the drug
  • Isolated silymarin is particularly suitable (for example, DE 1 923 982, DE 1 767 666 (Madaus)).
  • Silymarin is a flavanolignan complex, i.e., polyhydroxyphenylchromanones, and was first isolated from the plant in the 1960s (Dissertation, Janiak Bernhard, June 1960, Berlin University of Applied Sciences (DE 2020407), Pelter A., Hänsel R., Tetrahedron Letters, 25, (1968)).
  • Silymarin is composed of a mixture of the flavanolignan complex I-IV; specifically, its primary components are the four flavanolignans: silybin (silybinin) (silymarin I), silydianin (silymarin II), and silychristin (silymarin III)
  • dehydrosilybin 3-desoxysilychristin, desoxysilydianin (silymonin), silyadrin, silybinom, silyermin, and neosilymerin.
  • the fruit of the milk thistle is used for preparing the extract.
  • Such extracts from milk thistle and methods for preparing same have previously been described in the prior art, for example as disclosed in DE 1 923 982, DE 29 14 330 (Madaus).
  • a dry extract a content of preferably 30-65% by weight silymarin (other content ranges are possible), the silymarin portion containing the following fractions:
  • Isosilibinin A and B (diastereomeric mixture, C 25 H 22 OH 10 , MW 482.4) and
  • the raw material in this case, the plant drug
  • the raw material is usually degreased, extracted, filtered, concentrated, and purified.
  • Such a composition allows a silymarin release rate of 30 to approximately 40% (measured in accordance with Ph. Eur. 5.7; 2.9.3 (01/2006:20903 as amended, for example using the basket method, paddle model).
  • the object is to provide an improved milk thistle fruit extract, in particular one having an advantageously improved silymarin release rate while maintaining the native character.
  • the aim is to prepare the extract essentially without additives, supplements, carrier substances, or wetting agents.
  • the object is achieved by providing a method for preparing a milk thistle fruit extract, whereby in the following steps:
  • the plant drug is extracted with a solvent having moderate polarity (for example, ethyl acetate, ethanol, acetone, methanol, optionally containing aqueous fractions), preferably at 40-80 degrees Celsius, particularly preferably 50-70 degrees Celsius, b.) separated, preferably filtered, c.) concentrated, preferably under vacuum with stirring, at a temperature less than 60 degrees Celsius, preferably less than 40 degrees Celsius, and c′) optionally washed with hot water, d.) combined with ethanol, preferably 96% ethanol or greater, or a solvent of similar polarity, and then combined with hexane or a solvent of similar polarity and concentrated, preferably at a pressure of 1-100 mbar, and the resulting ethanol-water phase is removed, e.) dried and optionally comminuted, f.) taken up in anhydrous alcohol, preferably ethanol, g.) optionally filtered and concentrated, and h.) dried and optionally comminuted
  • the invention further relates to a method for preparing a milk thistle fruit extract having a silymarin release rate of 80% or greater, wherein an extract having a silymarin content of 15-85% by weight, in particular 30-65% by weight, is taken up in anhydrous alcohol, optionally filtered and concentrated, and then dried and optionally comminuted.
  • the invention therefore relates to a novel milk thistle fruit extract or flavanolignan preparation having an essentially amorphous crystal modification (see comparative tests of the X-ray structural analysis in FIG. 1 ).
  • the invention further relates to a medicament composed of a milk thistle fruit extract according to the invention, or use thereof for treatment and prevention of liver and gall bladder dysfunction, in particular for toxic liver damage (fatty liver, alcohol), hepatoses such as mushroom poisoning, acute liver failure, liver necrosis, liver dystrophy, cirrhosis of the liver, hepatic fibrosis, hepatomegaly, and fatty liver degeneration, liver insufficiency, and hepatitis, in particular hepatitis C.
  • toxic liver damage fatty liver, alcohol
  • hepatoses such as mushroom poisoning, acute liver failure, liver necrosis, liver dystrophy, cirrhosis of the liver, hepatic fibrosis, hepatomegaly, and fatty liver degeneration, liver insufficiency, and hepatitis, in particular hepatitis C.
  • the invention further relates to a pharmaceutical formulation containing a medicament according to the invention composed of a milk thistle fruit extract according to the invention.
  • FIG. 1 is a graph that shows the altered crystal modification, based on a comparison of silibinin Ch.-B.: 194051 and silibinin Ch.-B.: 7085i, using X-ray structural analysis (conditions corresponding to Example 2);
  • FIG. 2 is a graph that illustrates the results obtained (conditions corresponding to Example 2) in the complete angular measurement range for Sample Ref. 7233i, using the anhydrous alcohol extraction step f.) of the invention, where the sample mixtures composed of crystalline and amorphous phases were used;
  • FIG. 3 is a graph that illustrates the results obtained (conditions corresponding to Example 2) in the complete angular measurement range for Sample Ref. 7232i, not using the anhydrous alcohol extraction step f.) of the invention, where the sample mixtures composed of crystalline and amorphous phases were used.
  • one aspect of the present invention is method for preparing a milk thistle fruit extract, whereby in the following steps:
  • the plant drug is extracted with a solvent having moderate polarity (for example, ethyl acetate, ethanol, acetone, methanol, optionally containing aqueous fractions), preferably at 40-80 degrees Celsius, particularly preferably 50-70 degrees Celsius, b.) separated, preferably filtered, c.) concentrated, preferably under vacuum with stirring, at a temperature less than 60 degrees Celsius, preferably less than 40 degrees Celsius, and c′) optionally washed with hot water, d.) combined with ethanol, preferably 96% ethanol or greater, or a solvent of similar polarity, and then combined with hexane or a solvent of similar polarity and concentrated, preferably at a pressure of 1-100 mbar, and the resulting ethanol-water phase is removed, e.) dried and optionally comminuted, f.) taken up in anhydrous alcohol, preferably ethanol, g.) optionally filtered and concentrated, and h.) dried and optionally comminuted
  • the additional step f.) results in a significant increase in the silymarin release rate to 80% (see comparative examples). This is particularly advantageous, since a lower dosage of the milk thistle fruit extract according to the invention is achieved. It is also advantageous that a quality is attained which in the prior art is achievable only using additives, supplements, carrier substances, and wetting agents.
  • anhydrous alcohol in step f.) preferably includes C1-C4 alcohols, particularly preferably ethanol, such as 99% or even 99.5% pure.
  • the invention further relates to a method for preparing a milk thistle fruit extract having a silymarin release rate of 80% or greater, wherein an extract having a silymarin content of 15-85% by weight, in particular 30-65% by weight, is taken up in anhydrous alcohol, optionally filtered and concentrated, and then dried and optionally comminuted.
  • simarin refers to a substance mixture containing (at least) the four substances silybin, silydianin, silychristin, and isosilbin in various concentrations.
  • the ratios of these substances with respect to one another, and the presence of additional substances in the mixture, are not important. However, it is preferable that these substances meet the requirements of Ph. Eur. or DAB as amended. This is the case for the present invention.
  • a “silymarin release rate of 80% or greater” means that the active substances are at least 80% soluble in aqueous solution (standard according to Ph. Eur.; see examples).
  • the milk thistle fruit extract obtained is particularly suitable, in that as the result of method step f.) the crystalline fractions in the resulting extract are significantly reduced, and a milk thistle fruit extract having an essentially amorphous crystal modification is obtained.
  • the invention therefore relates to a novel milk thistle fruit extract or flavanolignan preparation having an essentially amorphous crystal modification (see comparative tests of the X-ray structural analysis in FIG. 1 ).
  • the invention relates to a novel milk thistle fruit extract or flavanolignan preparation composed of an amorphous crystal modification, wherein the crystalline fraction is less than 20%, preferably less than 10%, particularly preferably less than 7%, even 5%.
  • the invention therefore further relates to a medicament composed of a milk thistle fruit extract according to the invention, or use thereof for treatment and prevention of liver and gall bladder dysfunction, in particular for toxic liver damage (fatty liver, alcohol), hepatoses such as mushroom poisoning, acute liver failure, liver necrosis, liver dystrophy, cirrhosis of the liver, hepatic fibrosis, hepatomegaly, and fatty liver degeneration, liver insufficiency, and hepatitis, in particular hepatitis C.
  • toxic liver damage fatty liver, alcohol
  • hepatoses such as mushroom poisoning, acute liver failure, liver necrosis, liver dystrophy, cirrhosis of the liver, hepatic fibrosis, hepatomegaly, and fatty liver degeneration, liver insufficiency, and hepatitis, in particular hepatitis C.
  • the invention further relates to a pharmaceutical formulation containing a medicament according to the invention composed of a milk thistle fruit extract according to the invention.
  • the milk thistle fruit extracts according to the invention may be provided in the form of pharmaceutical preparations in dosage units.
  • the preparation [may] be present in the form of individual portions, for example tablets, dragees, capsules, pills, suppositories, and ampoules, the active substance content of which [may] correspond to a fraction or a multiple of a single dose.
  • the dosage units may contain, for example, 1, 2, 3, or 4 single doses, or 1 ⁇ 2, 1 ⁇ 3, or 1 ⁇ 4 of a single dose.
  • a single dose preferably contains the quantity of active substance which is dispensed in one administration, and which typically corresponds to a whole daily dose or a half, third, or fourth of a daily dose.
  • Nontoxic, inert, pharmaceutically suitable carrier substances are understood to mean solid, semisolid, or liquid diluents, fillers, and formulation adjuvants of all types.
  • Tablets, dragees, capsules, pills, granules, suppositories, solutions, syrups, suspensions, and emulsions are named as preferred pharmaceutical formulations.
  • Tablets, dragees, capsules, pills, and granules may contain the active substance or substances in addition to the customary carrier substances, such as a) fillers and extenders, for example starches, lactose, sucrose, glucose, mannite, and silicic acid, b) binders, for example carboxymethylcellulose, alginates, gelatins, and polyvinylpyrrolidone, c) humectants, for example glycerin, d) disintegrants, for example agar-agar, calcium carbonate, and sodium carbonate, e) solubility retardants, for example paraffin, f) absorption accelerators, for example quatenary ammonium compounds, g) wetting agents, for example cetyl alcohol and glycerin monostearate,
  • Tablets, dragees, capsules, pills, and granules may be provided with customary coatings and shells optionally containing opacifying agents, and may also have a composition such that they deliver the active substance or substances only in the intestinal tract or preferably in a specific portion thereof, optionally in a delayed manner, wherein polymeric substances and waxes, for example, may be used as encapsulating compounds.
  • the active substance or substances may also be present in microencapsulated form, optionally with one or more of the above-referenced carrier substances.
  • suppositories may contain customary water-soluble or water-insoluble carrier substances, for example polyethylene glycols, fats, for example cocoa butter, and higher esters (for example, C14 alcohol with C16 fatty acid), or mixtures of these substances.
  • customary water-soluble or water-insoluble carrier substances for example polyethylene glycols, fats, for example cocoa butter, and higher esters (for example, C14 alcohol with C16 fatty acid), or mixtures of these substances.
  • solutions and emulsions may contain customary carrier substances such as solvents, solubilizers, and emulsifiers, for example water, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils, in particular cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, and sesame oil, glycerin, glycerin formal, tetrahydrofurfuryl alcohol, polyethylene glycols, and fatty acid esters of sorbitan, or mixtures of these substances.
  • solvents such as solvents, solubilizers, and emulsifiers
  • solvents such as solvents, solubilizers, and emulsifiers
  • solvents such as solvents, solubilizers, and emulsifiers
  • solvents such as solvents
  • suspensions may contain customary carrier substances such as liquid diluents, for example water, ethyl alcohol, and propylene glycol, suspension agents, for example ethoxylated isostearyl alcohols, polyoxyethylene sorbite, and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, and gum tragacanth, or mixtures of these substances.
  • the referenced formulation forms may also contain dyes, preservatives, and fragrance- and taste-enhancing additives, for example peppermint oil and eucalyptus oil, and sweeteners, for example saccharin.
  • Comparative extracts (silibinin Ch.-B.: 194051, Ch.-B.: 7085i) according to the above description were prepared, silibinin Ch.-B.: 7085i being prepared according to additional method step f.).
  • step f. treatment with anhydrous ethanol in step f. causes the previously poorly soluble silibinin mixture, composed of an amorphous and crystalline structure, to be converted to an amorphous crystal modification (see FIG. 1 ) (i.e., the crystal lattice structure is altered), resulting in improved solubility and active substance release.
  • This additional method step allows preparation of the above-described extract having an active substance release of at least 80% total silymarin, calculated as silibinin (HPLC—Ph. Eur. 01/2007:2071), after 30 min, since this method improves the solubility not only of the silibinin, but also of the other silymarin isomers.
  • FIG. 1 shows the altered crystal modification, based on a comparison of silibinin Ch.-B.: 194051 and silibinin Ch.-B.: 7085i, using X-ray structural analysis (conditions corresponding to Example 2).
  • Radiographic analyses were carried out on an X'Pert Pro MPD diffractometer from PANalytical B.V., using Bragg-Brentano geometry and an X'Celerator detector.
  • PANalytical X'Pert PRO MPD diffractometer with a 9/9 goniometer having a radius of 240 millimeters, parallel lens with hybrid monochromator, and transfer geometry with sample holders for capillaries, with a spinner.
  • X'Celerator measuring unit having an active length of 2122.
  • Flushing 29 of 3 to 60° 29 having a step size of 0.017 and a measurement time of 1500 sec per step.
  • the rate of crystallization is the weight percentage of the crystalline phase in a sample mixture composed of crystalline and amorphous phases, using a crystallization index Ci:
  • Ci 100[Xc/(Xa+Xc)], where Xc represents the weight fraction of the amorphous phases.
  • the values of Xc were determined from the sum of the regions of all narrow points (in the crystalline phase) in the angular range of the study.
  • the values of Xa were obtained by determining the regions of wide points or “halos” (in the amorphous phase).
  • FIGS. 2 and 3 illustrate the diagrams obtained in the complete angular measurement range. Sample mixtures composed of crystalline and amorphous phases were used.
  • the resulting Ci values were 7% for sample Ref. 7233i (see FIG. 2 ), and were 24% for sample Ref. 7232i (see FIG. 3 ).

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Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
DE102007063115.6 2007-12-23
DE102007063115 2007-12-23
DE102008039271A DE102008039271A1 (de) 2007-12-23 2008-08-23 Neuer Mariendistelextrakt, Verfahren zur Herstellung und Verwendung
DE102008039271.5 2008-08-23
PCT/DE2008/002117 WO2009080006A2 (de) 2007-12-23 2008-12-23 Neuer mariendistelextrakt, verfahren zur herstellung und verwendung

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JP (2) JP5442632B2 (pt)
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AU (1) AU2008340922B2 (pt)
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Cited By (3)

* Cited by examiner, † Cited by third party
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US20120108825A1 (en) * 2009-05-14 2012-05-03 Euromed S.A. Amorphous silibinin for the treatment of viral hepatitis
CN104651037A (zh) * 2014-01-17 2015-05-27 吴长军 一种亚临界流体萃取水飞蓟籽仁中油脂和蛋白的方法
ES2706008A1 (es) * 2017-09-22 2019-03-27 Euromed S A Solubilidad mejorada del extracto de cardo mariano

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CN102225085B (zh) * 2011-06-20 2012-09-05 黑龙江大学 一种从水飞蓟秸秆中提取水飞蓟总黄酮的方法
KR101316806B1 (ko) * 2011-08-02 2013-10-10 (주)이뮤노텍 글루타치온과 실리마린을 유효성분으로 함유하는 항산화 및 간보호용 조성물
KR101655396B1 (ko) * 2013-08-06 2016-09-08 에스케이바이오랜드 주식회사 수용성 밀크씨슬 추출물 및 이의 제조방법
JP2015113332A (ja) * 2013-12-16 2015-06-22 花王株式会社 生薬粉体
CN104744447B (zh) * 2013-12-31 2017-12-26 天士力制药集团股份有限公司 水飞蓟宾迷迭香酸酯及其制备方法和用途
CN105622594B (zh) * 2016-03-17 2019-05-17 江苏中兴药业有限公司 一种高纯度水飞蓟素的制备方法
KR102242002B1 (ko) 2019-02-21 2021-04-19 주식회사 노바케이메드 동충하초균사체로 고상발효된 홍삼 추출물을 유효성분으로 함유하는 지방간 질환 예방 또는 치료용 조성물
CN111518090B (zh) * 2020-05-12 2021-08-10 沈阳药科大学 黄烷黄酮衍生物及其制备方法和用途
KR102669644B1 (ko) * 2023-06-27 2024-05-27 한국자연한방 주식회사 실리마린 생체이용률이 증대된 밀크씨슬 추출물을 포함하는 지방간 개선, 예방 또는 치료용 조성물

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